Genetic variants for head size share genes and pathways with cancer

Cell Reports Medicine, Год журнала: 2024, Номер 5(5), С. 101529 - 101529

Опубликована: Май 1, 2024

The size of the human head is highly heritable, but genetic drivers its variation within general population remain unmapped. We perform a genome-wide association study on (N = 80,890) and identify 67 loci, which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, most have widespread effects. Gene set enrichment observed for various cancers p53, Wnt, ErbB signaling pathways. Genes harboring lead enriched macrocephaly syndrome genes (37-fold) high-fidelity cancer (9-fold), not seen height variants. Head also near preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary expansion. Our results indicate regulating early cranial growth incline neoplasia later life, irrespective height. This warrants investigation clinical implications link between cancer.

Язык: Английский

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Gut microbiome features associated with liver fibrosis in Hispanics, a population at high risk for fatty liver disease

Hepatology, Год журнала: 2021, Номер 75(4), С. 955 - 967

Опубликована: Окт. 11, 2021

Hispanics are disproportionately affected by NAFLD, liver fibrosis, cirrhosis, and HCC. Preventive strategies noninvasive means to identify those in this population at high risk for urgently needed. We aimed characterize the gut microbiome signatures related biological functions associated with fibrosis environmental genetic factors affecting them.

Язык: Английский

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Gut Microbiome Alterations Associated with Diabetes in Mexican Americans in South Texas

mSystems, Год журнала: 2022, Номер 7(3)

Опубликована: Апрель 28, 2022

The gut microbiome composition varies across ethnicities and geographical locations, yet studies on diabetes-associated changes specific to high-risk Mexican Americans are lacking. Here, we aimed identify alterations associated with diabetes in this population, as well host genetic factors that may explain increased disease susceptibility ethnic group.

Язык: Английский

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Association between HSPA8 Gene Variants and Ischemic Stroke: A Pilot Study Providing Additional Evidence for the Role of Heat Shock Proteins in Disease Pathogenesis

Genes, Год журнала: 2023, Номер 14(6), С. 1171 - 1171

Опубликована: Май 27, 2023

HSPA8 is involved in many stroke-associated cellular processes, playing a pivotal role the protein quality control system. Here we report results of pilot study aimed at determining whether SNPs are linked to risk ischemic stroke (IS). DNA samples from 2139 Russians (888 IS patients and 1251 healthy controls) were genotyped for tagSNPs (rs1461496, rs10892958, rs1136141) gene using probe-based PCR. SNP rs10892958 was associated with an increased (risk allele G) smokers (OR = 1.37; 95% CI 1.07–1.77; p 0.01) low fruit vegetable consumption 1.36; 1.14–1.63; 0.002). rs1136141 also A) exclusively 1.68; 1.23–2.28; 0.0007) intake 1.29; 1.05–1.60; 0.04). Sex-stratified analysis revealed association males G; OR 1.30; 1.05–1.61; 0.01). Thus, represent novel genetic markers IS.

Язык: Английский

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Resolving mechanisms of immune‐mediated disease in primary CD 4 T cells

EMBO Molecular Medicine, Год журнала: 2020, Номер 12(5)

Опубликована: Апрель 1, 2020

Article1 April 2020Open Access Transparent process Resolving mechanisms of immune-mediated disease in primary CD4 T cells Christophe Bourges Cambridge Institute Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Campus, University Cambridge, UK Department Medicine, School Clinical Addenbrooke's Hospital, Search for more papers by this author Abigail F Groff Stem Cell Regenerative Biology, Harvard University, MA, USA Oliver S Burren Chiara Gerhardinger Kaia Mattioli Anna Hutchinson MRC Biostatistics Unit, Public Health, Theodore Hu Tanmay Anand Madeline W Epping Chris Wallace Kenneth GC Smith John L Rinn orcid.org/0000-0002-7231-7539 Biochemistry, BioFrontiers Institute, Colorado, Boulder, CO, James C Lee Corresponding Author [email protected] orcid.org/0000-0001-5711-9385 Information Bourges1,2, Groff3, Burren1,2, Gerhardinger3, Mattioli3, Hutchinson4, Hu1,2, Anand1,2, Epping1,2, Wallace1,3, Smith1,2, Rinn3,5 *,1,2,3 1Cambridge 2Department 3Department 4MRC 5Department *Corresponding author. Tel: +44 1223 767063; E-mail: EMBO Mol Med (2020)12:e12112https://doi.org/10.15252/emmm.202012112 PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments responses to feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Deriving from GWAS data remains formidable challenge, with attempts identify causal variants being frequently hampered strong linkage disequilibrium. To determine whether could be identified their functional effects, we adapted massively parallel reporter assay use cells, cell type whose regulatory DNA is most enriched SNPs. This enabled effects candidate SNPs examined relevant cellular context generated testable hypotheses into mechanisms. illustrate power approach, investigated locus that has been linked six diseases but cannot fine-mapped. By studying lead expression-modulating SNP, uncovered an NF-κB-driven circuit which constrains T-cell activation through dynamic formation super-enhancer upregulates TNFAIP3 (A20), key NF-κB inhibitor. In activated feedback disrupted—and prevented—by risk variant at leading unrestrained via molecular mechanism appears broadly predispose human autoimmunity. Synopsis Little progress made resolving SNPs, genes loci. An massively-parallel (MPRA) allows study loci cell-type highly disease-associated Adapted MPRA identifies putative based on within cells—key effectors disease. These differ those detected Jurkat cell-line, reinforcing importance appropriate disease-related studies. The results provide focus mechanistic studies resolve downstream consequences multiple At gene-desert diseases, SNP shown abrogate binding, disrupt formation, reduce expression, cell-driven inflammation. provides insights biology fine-mapped illustrates potential method uncover genetic paper explained Problem Genome-wide association (GWAS) have hundreds regions genome are involved pathogenesis these drive remain largely unknown. Identifying variants, biological mediate risk, important first step fine-mapping efforts frustrated disequilibrium (LD), leaving unresolved unfulfilled. Results describes development cells—the using gene deserts range simultaneously non-coding show how can effects. We approach autoimmune investigating thus uncovering Impact Our work generalisable distil haplotypes down specific disease-relevant cells. generates applied any overlaps elements biology, framework considerable finally realised. Introduction Hundreds implicated inflammatory effect unknown (Claussnitzer et al, 2020). refine associations statistical do only minority resolved (Farh 2015; Huang 2017). Other methods sought re-weight enrichment genomic (e.g. tissue-specific marks; Schaub 2012; Shooshtari 2017), not assess consequences, nor reveal contributes leaves majority either or unresolvable, ambition identifying unrealised (Visscher compound gene(s) affected confirmed Many associated haplotypes, example, contain little evidence one causally involved, while other entirely located intergenic (or "gene deserts") often reported lack genes. Most attributable variation rather than coding sequence, significant enhancers, particularly super-enhancers—large enhancer clusters usually type-specific control expression state (Hnisz 2013). Testing individual transcription—as means refining variants—would bypass limitations LD directly mediates was previously laborious expensive. high-throughput assays activity, such as (MPRAs), now possible. MPRAs test activity large numbers short sequences coupling each barcoded (Melnikov 2012). normalising RNA barcode counts transfected equivalent input plasmid library, modulate various settings (Tewhey 2016; Ulirsch 2016). A feature MPRAs, however, determined transcription factors present so misleading if inappropriate used. date, almost all performed lines, part because easy culture transfect. It widely recognised, poor surrogates types immune (Astoul 2001; Bartelt 2009). Here, adapt resting stimulated 2015). testing 14 generate basis exploring underlying yield unappreciated variation. pleiotropic 6q23 locus, example whereby common variant—identified its cells—disrupts pathway normally limits super-enhancer. Disruption releases intrinsic brake reveals multi-disease-associated haplotype change would appear pervasively Adaptation designed (all r2 ≥ 0.8 SNP) 10 (Fig 1A, Table 1; Trynka 2011; Cooper Eyre Jostins Tsoi International Genetics Ankylosing Spondylitis 2013; Multiple Sclerosis Liu Onengut-Gumuscu Several Gene were selected (i) less known about compared containing genes, (ii) (such splicing effects) unlikely account associations, (iii) many epigenetic marks consistent maximise tested around three overlapping constructs every allele (Ulirsch 2016) synthesised extra oligonucleotides combinations alleles assayed same construct. also included tiled 50 bp intervals activity—and enable us exclude lacked this. Figure 1. Development A. Experimental workflow MPRA: oligonucleotide library cloned empty vector, promoter inserted restriction sites oligonucleotide. assembled extracted after 24 h. normalised respective (DNA), sequenced separately. B. incorporating RSV promoter. C. Principal component analysis scaled element (sum barcodes tagging construct mRNA) 12 donors. Dotted lines indicate samples donor. D. Heat maps showing pairwise comparison (mRNA/DNA) between donors—left panel: cells; right Download figure PowerPoint Autoimmune tag Chr. Associated disease(s) Distance nearest (kb) Number (r2 0.8) Haplotype block size rs883220 – 1p34 RA 102.3 9 30.2 rs6759298 (AS) rs10865331 (Ps) 0.86 2p15 AS, Ps 99.5 33.9 rs1534422 2p24 ATD 208.2 15.9 rs1813375 3p24 MS 203.9 15 10.9 rs2611215 4q32 T1D 139.4 20 16.7 rs12186979 5p13 AS 59.7 5 97.8 rs17119 6p23 UC, CD, 512.1 44 22.6 rs2327832 (SLE) rs6920220 (rest)a 0.92 RA, CeD, SLEb, T1Dc 143.6 47.5 rs1991866 8q24 CD 136.2 28 22.0 rs2456449 219.3 17 19.5 rs4409785 11q21 ATD, vitiligod 181.2 3 9.7 rs1456988 14q32 1,086.9 38 14.0 rs1297258 21q21 274.0 24.1 rs2836883 (AS, PSC) rs2836878 (UC, CD) 1.0 21q22 PSC, 87.1 13 5.8 ankylosing spondylitis; thyroid disease; coeliac Crohn's Chr., chromosome; MS, sclerosis; Ps, psoriasis; sclerosing cholangitis; rheumatoid arthritis; SLE, systemic lupus erythematosus; single nucleotide polymorphism; T1D, 1 diabetes; ulcerative colitis. Genetic published immunochip data. For extended (LD region tagged side) does well-characterised represents 0.8. CeD rs17264332 = rs6920220). b Association subsequently (Langefeld c P < × 10−5 obtain Bayesian posterior probability given (Onengut-Gumuscu d Vitiligo GWAS, (Jin After assembly, healthy donors Materials Methods) no (Appendix Fig S1A B). confirming successful transfection had occurred S1B), surmised minimal promoter, conventionally used MPRA, may insufficient initiate line-based studies, stronger promoters produce comparable obtained (Ernst Ferreira therefore screened series S1C) Rous sarcoma virus (RSV) incorporation vector 1B) robustly initiated preclude further amplification. replicates (donors) ensure reproducible, differences composition reduced expected h, GFP quantify sequencing S1D). pre-processing, collapsed (Materials Methods). Using principal analysis, found responsible much total variance 1C) transcriptional constructs—calculated library—correlated well individuals 1D). detect QuASAR-MPRA (Kalita 2018; 2A) combined donor fixed-effects meta-analysis Significant 8/10 positive (comprising five 2016), two eQTLs 2015) synthetic included/disrupted canonical factor binding site; 2B). Enhancer tiling negative controls S1, observed correlated S1E), did correlate (an immortalised line)—reinforcing value model when S1F). validate haplotype, allele-specific complementary luciferase-based system 2C). Despite different quantification method, luciferase (Pearson r 0.87)—indicative genuine likely physiologically 2D). prioritised means, silico variants—DeepSEA (Zhou Troyanskaya, RegulomeDB (Dong Boyle, 2019; Dataset EV1). Considering approaches together, predicted functionally 3/14 (2 DeepSEA, RegulomeDB). DeepSEA significant, (most cells). remaining eight loci, effect—consistent better predicting 2019) highlighting Altogether, reflect 2. Allele-specific qq plots −log10(P) values versus under null hypothesis representative samples. Activity GATA1, RUNX1 include site indicated (+) disrupted (−). Fixed-effects shown: * 0.05; ** 0.01, *** 0.001, **** 0.0001. Box whisker represent median IQR (box) min max (whiskers). Exact Appendix S4. validation experiment (EF1α), (luciferase) (qPCR). Expression-modulating [log2(OR)] measured experiments. OR calculated allelic presented respect (luciferase: n 5, 12). establishing next Figs S2 S3, Datasets EV2 EV3). bowel (IBD)-associated variant, rs1736137 (Huang both IBD-risk consistently increasing 3A). As proof principle, spondylitis-associated where corrected coverage estimates resolves 99% credible set (rs6759298, rs4672505 rs13001372). (rs6759298) others negligible 3B)—thus variant. 3. Pie chart depicting 2017; probabilities) IBD-associated (left panel). (centre panel) (right effect. AS-associated (righ

Язык: Английский

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The landscape of host genetic factors involved in immune response to common viral infections

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2020, Номер unknown

Опубликована: Май 7, 2020

ABSTRACT Introduction Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the mechanisms of immune response to viral infection provides insight into disease etiology therapeutic opportunities. Methods We conducted comprehensive study including genome-wide transcriptome-wide association analyses identify loci associated with immunoglobulin G antibody 28 antigens 16 using serological data from 7924 European ancestry participants UK Biobank cohort. Results Signals human leukocyte antigen (HLA) class II region dominated landscape response, 40 independent 14 classical alleles, 7 which exhibited pleiotropic effects across families. identified specific amino acid (AA) residues that are seroreactivity, strongest associations presented range AA positions within DRβi at 11, 13, 71, 74 Epstein-Barr Virus (EBV), Varicella Zoster (VZV), Human Herpes virus 7, (HHV7) Merkel cell polyomavirus (MCV). Genome-wide discovered novel outside HLA ( P <5.0×10 -8 ), FUT2 (19q13.33) BK (BKV), STING1 (5q31.2) MCV, as well CXCR5 (11q23.3) TBKBP1 (17q21.32) HHV7. Transcriptome-wide 114 genes infection, 12 region, ECSCR : P=5.0*10 -15 (MCV), NTN5: P=1.1×10 -9 P2RY13: EBV nuclear antigen. also demonstrated pleiotropy between diseases; autoimmune disorders cancer neurodegenerative psychiatric conditions. Conclusions Our confirms importance elucidates determinants beyond contribute host-virus interaction.

Язык: Английский

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SERPINE1 mRNA Binding Protein 1 Is Associated with Ischemic Stroke Risk: A Comprehensive Molecular–Genetic and Bioinformatics Analysis of SERBP1 SNPs

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(10), С. 8716 - 8716

Опубликована: Май 13, 2023

The SERBP1 gene is a well-known regulator of SERPINE1 mRNA stability and progesterone signaling. However, the chaperone-like properties have recently been discovered. present pilot study investigated whether SNPs are associated with risk clinical manifestations ischemic stroke (IS). DNA samples from 2060 unrelated Russian subjects (869 IS patients 1191 healthy controls) were genotyped for 5 common SNPs—rs4655707, rs1058074, rs12561767, rs12566098, rs6702742 SERBP1—using probe-based PCR. association SNP rs12566098 an increased (risk allele C; p = 0.001) was observed regardless gender or physical activity level modified by smoking, fruit vegetable intake, body mass index. rs1058074 C) exclusively in women (p 0.02), non-smokers 0.003), low 0.04), consumption BMI ≥25 0.007). rs12561767 0.01), 0.036), rs4655707 0.04) shortening activated partial thromboplastin time. Thus, represent novel genetic markers IS. Further studies required to confirm relationship between polymorphism risk.

Язык: Английский

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C9orf16 (BBLN) gene, encoding a member of Hero proteins, is a novel marker in ischemic stroke risk

RESEARCH RESULTS IN BIOMEDICINE, Год журнала: 2022, Номер 8(3)

Опубликована: Сен. 19, 2022

Background: Ischemic stroke (IS) is the leading cause of death and disability worldwide. Chaperone proteins protect brain cells from ischemic damage by restoring structures damaged proteins. C9orf16 (also known as BBLN) belongs to class heat-resistant obscure (HERO) proteins, characterized ability stabilize various suppress neurotoxicity reduce proteotoxic stress. In this regard, it may play a potentially significant role in risk development clinical manifestations IS. The aim study: To investigate an association between single nucleotide polymorphism rs2900262 gene encoding predisposition Materials methods: A total 897 patients with IS 1140 healthy controls were recruited for study. Genotyping was done using probe-based genotyping assay. Multiple logistic regression analysis performed evaluate associations genotypes events. Dominant, recessive additive models analyzed. Adjustment sex, age, smoking throughout. Benjamini-Hogberg false-discovery rate used correct multiple comparisons. Results: rs2900262*T allele found be associated increased exclusively females (dominant model: OR=1.74, 95% CI=1.07-2.82, PFDR=0.042; OR=1.69, CI=1.06-2.71, PFDR=0.042). Additional showed that smokers only OR=1.92, CI=1.09-3.37, OR=1.79, 95%CI=1.04-3.08, Also, we demonstrated C/T-T/T genotype carriers exhibit earlier manifestation (59.53±1.12 years) compared C/C (61.63±0.4 years); mean difference=-1.98; CI=-3.61 – -0.36; PFDR=0.026. Conclusion: This study first world demonstrate possible contribution stroke.

Язык: Английский

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Rare variant association testing in the non-coding genome

Human Genetics, Год журнала: 2020, Номер 139(11), С. 1345 - 1362

Опубликована: Июнь 4, 2020

Язык: Английский

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Classification of PRSS1 variants responsible for chronic pancreatitis: An expert perspective from the Franco-Chinese GREPAN Study Group

Pancreatology, Год журнала: 2023, Номер 23(5), С. 491 - 506

Опубликована: Апрель 20, 2023

Язык: Английский

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